Exam 3 Flashcards
What are the 3 regions of the brain?
Hindbrain
Forebrain
Midbrain
What are the components of the hindbrain?
Medulla
Pons
Cerebellum
What are the components of the midbrain?
substantia nigra
What are the components of the forebrain?
Cerebral cortex
Basal ganglia (striatum, globus pallidus, subthalamic nucleus)
Limbic system (hippocampus, amygdala)
Diencephalon (thalamus, hypothalamus)
What structures are associated with the forebrain?
“higher” structures
What are the functions of the medulla?
Autonomic functions (involuntary)
Controls: respiration, cardiac function, vasomotor responses, reflexes (coughing, etc)
What are the functions of the pons?
Acts as a “bridge” between the cerebellum and the forebrain
-relays signals from the forebrain to the cerebellum
What are the functions of the cerebellum?
“little brain”
Governs motor coordination for producing smooth movements
What is an important point to remember about cerebellum neurodegeneration?
Undergoes neurodegeneration in spinocerebellar ataxias
(causes disjointed or jerky movements “ataxias”)
*how we know if this area is damaged
What are the two parts of the substantia nigra?
SN pars compacta
SN pars reticulata
What is the function of the SN pars compacta?
Provides INPUT to the basal ganglia
*supplies dopamine to the striatum (goes wrong in Parkinson’s)
-Voluntary motor control and cognitive functions
What part of the midbrain is involved in the development of Parkinsons disease?
SN pars compacta
-The supply of dopamine by this area to the striatum gets interrupted
-This area undergoes neurodegeneration in Parkinsons
What is the function of the SN pars reticulata?
Output function
Relays signals from the basal ganglia to the thalamus
What is the function of the cortex (cerebrum)?
Processing and interpreting information
-decision making, higher level functions
What is the function of the basal ganglia?
Voluntary motor control
Some cognitive functions
What are the two parts of the limbic system?
Amygdala
Hippocampus
What is the function of the amygdala?
Emotions
What is the function of the hippocampus?
Memory
What are the two parts of the diencephalon?
Thalamus
Hypothalamus
What is the function of the thalamus?
“Relay station” to and from the cortex
What are the functions of the hypothalamus?
Controls involuntary functions
-Internal homeostasis
-Emotions
-Hormonal control
-Direct neural regulation
Which structures are associated with controlling involuntary functions?
Medulla
Hypothalamus
Which structures are associated with controlling voluntary functions?
SN pars compacta (movement with intention)
Basal ganglia
What is a cortico-thalamic loop?
The senses receive information about the environment and pass it through the thalamus to the cortex and then back
-This loop makes decisions about how to interpret and react to the incoming sensory information
*What area of the brain is schizophrenia associated with?
Frontal cortex
Which of the following brain structures is directly involved in controlling involuntary functions?
A. hypothalamus
B. thalamus
C. medulla oblongata
D. A, B, and C
E. A and C
E.
hypothalamus and medulla
What are the 3 functions of astrocytes?
-Provide neurons with growth factors + antioxidants
-Remove excess glutamate
–Support the blood-brain barrier
Why is it important for astrocytes to remove glutamate?
Too much glutamate leads to excess calcium which overwhelms mitochondria
-mitochondria spit out free radicals which leads to cell death
(too much glutamate is toxic)
What is the function of oligodendrocytes?
Produce myelin sheath that insulates axons
What are the 3 functions of microglia?
-Provide growth factors
-Clear debris through phagocytosis
-Neuroinflammation
What is an important point to remember about microglia’s function?
They are PRO-INFLAMMATORY
What is the overarching role of microglia that makes them easier to remember?
They are the “immune cells of the brain”
Which of the glial cells make up the blood-brain barrier?
Astrocytes
How does the blood-brain barrier act as a barrier?
Cells are held very tight together by tight junctions leaving no spaces between them
-this is what forms the barrier since it is too tight to cross
What triggers neurotransmission?
Electrical depolarization of the neuron
(influx of Na+)
At the beginning of an action potential, is the inside of the cell positive or negative?
Negative
-why it is below threshold to start
True or False: an action potential leading to neurotransmitter release will only occur when threshold is reached or passed
True
What causes repolarization?
Action potentials open to move K out of the cell
Cl- moves into cell
-this reestablishes the original negative charge
What is an afterpotential?
The action potential dips below resting potential between repolarization and depolarization
(an overshoot of repolarization)
**part of the refractory period
How long do action potentials last?
0.2-0.5 msec
What is a refractory period?
The period after an action potential when a neuron will not fire again
(hyperpolarized phase)
True or False: The magnitude of an action potential will always be the same for a single neuron
True
*the height of the action potential spike on a graph of them will always be the same
What happens when we apply an excitatory neurotransmitter?
Action potentials occur more frequently
*depolarizing
What happens when we apply an inhibitory neurotransmitter?
Action potentials occur less frequently
*polarizing
Why is the current carried by a nerve fiber (bundle of axons) greater?
Summation
What are EPSP’s?
Excitatory postsynaptic potentials
*weak signals that do not clear the threshold
-induced by excitatory neurotransmitters
What are IPSP’s?
Inhibitory postsynaptic potentials
*these lower the polarity far below baseline so that it is harder to clear the threshold and produce an action potential
How does an excitatory neuron cause an Excitatory Postsynaptic Potential?
Allows Na+ ions to cross the membrane
How does an inhibitory neurotransmitter induce hyperpolarization?
Allows Cl- ions to cross the membrane
What is hyperpolarization?
When a cell is so negative that it is below the resting potential
True or False: an IPSP can decrease the magnitude of an EPSP
True
-because an IPSP makes it harder to reach the threshold
-even though EPSP’s do not reach the threshold, they still will lower and farther away from the threshold than normal
NOTE
Review lecture 1 slide 20
What are the 3 common amino acid neurotransmitters?
GABA*
Glycine
Glutamate*
*= focus in CNS
What are the 2 types of GABA receptors?
GABA (A)
GABA (B,C)
What type of receptor is GABA (A)?
Ion channel
What type of receptor is GABA (B)?
GPCR
What is GABA?
The major inhibitory neurotransmitter in the brain
-depresses neuronal excitability (by increasing Cl- influx)
What drugs interact with GABA?
CNS depressants
-Sedative hypnotics
-Anticonvulsants
-Anxiolytics
What kind of neurotransmitter is GABA?
Inhibitory
-hyperpolarizes the neuron
What conditions are affected by GABA?
Epilepsy
Spasticity
Addiction/Alcohol
*What is glycine?
Similar to GABA
*but acts in the spinal cord
What are the 3 Glutamate Receptors?
AMPA, NMDA (ion channel)
mGluR (GPCR)
What is glutamate?
EXCITATORY neurotransmitter in the brain
How can excess glutamate cause neuronal damage?
By allowing excessive Ca+ influx into the neuron
(overexcites the neuron, leads to cell death)
What disease states are associated with glutamate?
Epilepsy
Schizophrenia
Which neurotransmitter (GABA or Glutamate) is excitatory and which is inhibitory?
GABA: inhibitory
Glutamate: excitatory
What are the 4 common non-amino acid neurotransmitters?
-Acetylcholine
-Dopamine (DA)
-Norepinephrine
-Serotonin (5-HT)
What are the two types of acetylcholine receptors?
Nicotinic
Muscarinic
Where do acetylcholine receptors act?
Periphery
-basal forebrain
-pons
-cortex
-basal ganglia
*What are examples of drugs that target acetylcholine transmission?
Cholinesterase inhibitors
-Aricept (used in Alzheimer’s disease)
What disease states are associated with acetylcholine?
Cognitive function/decline
Nicotine dependence
Movement disorders
What are the two dopamine receptors?
D1-like (GS coupled)
D2-like (Gi coupled)
What are the functions of the D1-like receptor and the D2-receptor?
D1-like: increase cAMP
**Gs coupled
D2-like: decrease cAMP
**Gi coupled
Drugs that block dopamine transmission can lead to what?
They increase extracellular dopamine concentrations which can produce euphoria and lead to addiction
(ex: cocaine, amphetamine)
Excessive dopaminergic signaling can contribute to which disease state?
Schizophrenia
Loss of dopamine neurons in the SN is responsible for which disease state?
Parkinson’s disease
What drugs interact with the dopamine pathways?
Antipsychotics (D2 receptor antagonists)
D2/D3 and D1 receptor agonists used in Parkinson’s disease
What disease states are associated with dopamine transmission?
Schizophrenia
Parkinson’s disease
Addiction
Depression
ADHD
Where does dopamine transmission occur?
Midbrain
-substantia nigra
-pars compacta
-ventral tegmental area (reward + addiction)
What are the receptors for norepinephrine?
a1, a2 (GPCR)
What are the drug targets of norepinephrine?
a- and B- adrenergic receptors
norepinephrine transporter (NET)
Norepinephrine transporter (NET) inhibitors are used to treat what disease state?
Depression
Where does norepinephrine transmission occur?
Pons
What disease states are associated with norepinephrine transmission?
-Memory
-Depression
-Addiction
-Pain
What are the 2 serotonin receptors?
5-HT3
5-HT1,2
Where does serotonin transmission occur?
Midbrain
Pons
**raphe nuclei in these areas produce serotonin
*What is the function of raphe nuclei?
Give rise to 5-HT axons
What drugs interact with 5-HT receptors?
5-HT2A antagonists (atypical antipsychotics)
SERT uptake inhibitors (depression)
5-HT2A agonists (hallucinogenic, ex: LSD)
What disease states are associated with serotonin transmission?
-Depression
-Mood disorders/anxiety
-Schizophrenia
What is multiple sclerosis (MS)?
An immune-mediated (inflammatory) disorder involving destruction of the myelin sheath surrounding neuronal axons
What are some areas in the body that are affected by MS?
-Optic nerve (vision)
-Corticospinal tract (fatigue)
-Cerebellum (walking problems)
-Sensory pathways (pain)
-Vestibular pathways (dizziness)
For an environmental insult to cause MS, what age must exposure occur AFTER?
15
How can viral or bacterial infections increase the risk of MS?
By activating autoreactive immune cells
-leads to an autoimmune response in genetically susceptible individuals
What specific virus may be involved in the development of MS?
Epstein-Barr Virus (EBV)
How can Epstein-Barr Virus (EBV) cause MS?
Sequence similarities between EBV and self-peptides can result in activation of autoreactive T or B cells
**molecular mimicry
Which antigen is responsible for the molecular mimicry of Epstein-Barr Virus in MS?
Epstein-Barr nuclear antigen (EBNA)
(resembles myelin basic protein, antigens recognize the host’s myelin basic protein)
**leads to myelin sheath destruction
How does MS demonstrate a gene-environment interaction?
Patients with a particular HLA phenotype have increased risk of developing MS when they also have anti-EBNA antibodies
The first time that an inflammatory demyelinating episode surpasses the clinical threshold is known as what?
CIS
Clinically Isolated Syndrome
After the CIS, if more inflammatory demyelinating episodes that surpass the clinical threshold occur what are these known as?
RRMS
Relapsing Remitting MS
When there are no more inflammatory demyelinating episodes but the underlying MS disease continues to progress this is called what?
SPMS
Secondary Progressive MS
**inflammatory part is less present but damage and symptoms continue
What % of MS cases are Relapsing-Remitting MS (RRMS)?
85%
What % of MS cases are Primary progressive MS (PPMS)?
15%
What is Primary Progressive MS (PPMS)?
Resembles SPMS
-mean age of onset is later (40)
True or False:
If a patient has Relapsing-Remitting MS (RRMS) they will never have Primary Progressive MS (PPMS)
True
NOTE
See lecture 2 sides 7+8
How is the overall clinical presentation of MS in a patient determined?
A combination of the underlying degeneration (uniform/progressive) AND the host’s immune reaction to it (intermittent/variable)
What are the 2 phases of MS?
Autoimmune
Degenerative
Which phase of MS is the disease trigger?
UNCLEAR
What is the function of dendritic cells?
Present CNS antigens
What is the pathophysiology of MS?
Dendritic cells present CNS antigens and activate T-cells
B and T cells proliferate and infiltrate the CNS using a4-integrin-mediated binding to penetrate the BBB
B cells mature to plasma cells after encountering an antigen, release antibodies
T cells interact with target ligands on MHC molecules, activate, and results in cytokine release and macrophage stimulation
This causes myelin sheath damage
What cells do T cells engage with in the MS autoimmune response?
Oligodendrocytes
*destroy these human cells
-antibodies trigger complement activation and cause pore formation and cell damage
-macrophages are recruited and release toxic agents
How do macrophages harm the myelin sheath?
The release of toxic agents and phagocytosis
Do action potentials travel faster or lower in myelinated regions of axons?
Faster
-due to the insulating effects of myelin
What happens to action potentials in the Node of Ranvier?
Action potentials slow down
-current density builds up
(note: this is a zone of demyelination)
Voltage-gated Na+ channels in the node of Ranvier are used to do what to action potentials?
Essential for replenishing action potentials
How does demyelination affect the propagation speed of action potentials?
Slows them down
How does remyelination occur?
Recruits OPCs (oligodendrocyte precursor cells) to the lesion
These turn into myelin-producing oligodendrocytes
Why does remyelination typically fail in MS?
Lack of OPCs or failure of OPCs to differentiate
What is astrogliosis?
Invasion and propagation of astrocytes that results in irreversible gliotic plaque formation or scars
What cells are activated by demyelination?
Microglia
Astrocytes
What is the function of microglia and astrocytes in remyelination?
Release pro-migratory factors and mitogens
-These recruit OPCs (oligodendrocyte precursors) to the lesion and stimulate their proliferation
What is the key step in remyelination that often fails in MS?
OPC differentiation
What are the 2 pathways that demyelinated axons can take?
Remyelination
Degradation
What is the function of immunomodulatory therapies in MS?
Interfere with T or B cell activation, proliferation, and binding to the BBB
What is the function of rescue strategies in MS?
Remyelination
What contrast agent is used to visualize MS brain lesions?
Gadolinium
What is Guillain-Barre Syndrome?
Acute, inflammatory neuropathy
-Starts as weakness in distal muscles and lower extremities and can progress to total paralysis with death from respiratory failure in days
-Caused by an autoimmune attack on peripheral nerves resulting in demyelination
What are the 3 categories of MS treatment?
- Treatment of Acute Attacks
- Disease-Modifying Therapies (DMTs)
- Symptomatic Therapies
What is the goal of disease-modifying therapies with MS?
-Reduce relapse rates
-Slow progression of disability
Are disease-modifying MS therapies used to treat relapsing or progressive forms of the disease more?
Relapsing
What are the 4 first-line agents for MS?
Interferon B1a (Avonex, Rebif)
Interferon B1b (Betaseron, Extavia)
Glatiramer Acetate (Copaxone)
Fingolimod (Gilenya)
What are the 2 second-line agents for MS?
Natalizumab (Tysabri)
Mitoxantrone (Novantrone)
What are the 3 new drugs for MS?
Teriflunomide (Aubagio)
Dimethyl fumarate (Tecfidera)
Cladribine (Mylinax)
What are the medications used for treatment of acute MS attacks?
Methylprednisolone
Prednisone
Adrenocorticotropic hormone (ACTH)
What are the 2 corticosteroids used for acute MS attacks?
Methylprednisolone
Prednisone
How do corticosteroids work for treatment of acute MS attacks?
Up-regulate anti-inflammatory genes
Down-regulate pro-inflammatory genes
Alleviate edema in demyelinated areas
Where do Interferon B1a and B1b work?
Periphery
BBB
What is the function of Interferon B1a and B1b in the periphery?
Inhibit autoreactive lymphocytes
(T cells, dendritic cells)
What is the function of Interferon B1a and B1b in the BBB?
Inhibit BBB penetration by decreasing matrix metalloproteinase (MMP)
What reduces the efficacy of Interferon B1a and B1b?
neutralizing antibodies
What is the MOA of Glatiramer acetate?
Synthetic polypeptide
Mimics antigenic properties of myelin basic protein
**Modulates antigen-presenting cells (dendritic cells) which leads to decreased T cell activation
What is the MOA of Fingolimod?
Sphingosine-1-phosphate (S1P) receptor agonist
-stimulates oligodendrocyte survival (remyelination)
[CNS]
-interferes with lymphocyte movement out of lymphoid organs
[Periphery]
What is an important side effect to note with Fingolimod?
-Progressive multifocal leukoencephalopathy (PML)
[potentially lethal brain infection]
What are considerations to make when deciding which first-line MS treatment to use?
Fingolimod is superior to interferon beta
*BUT Fingolimod has more side effects associated with it
What is the MOA of Natalizumab?
*2nd line
Monoclonal antibody specific for a4 integrin*
a4-integrin pairs with B1-integrin to produce “very late antigen” (VLA-4)
Inhibiting VLA-4 binding to its ligand (VCAM-1 on CNS vascular endothelium) interferes with B and T cell movement across the BBB into the CNS
(interferes with binding of B and T cells to the BBB and makes it difficult to cross)
What are some side effects to be aware of with Natalizumab?
Progressive multifocal leukoencephalopathy (PML)
Induces neutralizing antibody development which can cause allergic reactions
What is the MOA of Mitoxantrone?
*2nd line
Anthracenedione with CYTOTOXIC ACTIVITY
-reduces lymphocyte numbers by causing DNA strand breaks via intercalation
-Delays DNA repair via inhibition of topoisomerase II
When should Mitoxantrone be considered for use?
Secondary Progressive MS (SPMS)
**first cytotoxic drug approved for this
Also can be used for induction therapy and then replaced with 1st-line agent
Where does Mitoxantrone act?
Periphery
What is the MOA of Teriflunomide?
New agent
Cytotoxic agent
-Inhibits proliferation of peripheral lymphocytes (B and T)
Where does Teriflunomide act?
Periphery
What is the MOA of Dimethyl fumarate, Diroximel fumarate, and Monomethyl fumarate?
New Agents
Metabolized in the GI tract
-Activate Nrf2-mediated cellular antioxidant responses and anti-inflammatory pathways
-Promote remyelination
-Suppress activated T cells and dendritic cells in periphery
What is the active form:
Dimethyl fumarate Diroximel fumarate
Monomethyl fumarate
Monomethyl ester
Where do Dimethyl fumarate, Diroximel fumarate, and Monomethyl fumarate act?
Periphery
and
CNS
What side effect is a concern with Dimethyl fumarate, Diroximel fumarate, and Monomethyl fumarate?
Progressive multifocal leukoencephalopathy (PML)
Where does the Nrf2 antioxidant response pathway occur?
In astrocytes
What antioxidant degrades Nrf2?
Keap1
How does the Nrf2 pathway work?
Normally, Nrf2 is continually targeted for destruction by Keap1
When a cell is exposed to toxins or undergoes oxidative stress, Keap1 is covalently modified and cannot degrade Nrf2
Nf2 accumulates and enters the nucleus where it activates gene transcription regulated by the antioxidant response element (ARE)
These genes are involved in glutathione biosynthesis and detoxification
*Anti-oxidant and Anti-inflammatory
What is the MOA of Siponimod, Ozanimod, and Ponesimod?
New drugs
sphingosine-1-phosphate (S1P) receptor agonists
***Same as fingolimod
-oligodendrocyte survival
-remyelination
-interfere with lymphocyte movement out of lymphoid organs
When do we use Siponimod, Ozanimod, and Ponesimod?
Relapsing Remitting MS (RRMS)
Secondary progressive MS (SPMS)*
What is the MOA of Cladribine?
new drug
*Cytotoxic prodrug
Taken up into cells by purine nucleoside transporters
Damages DNA and interferes with DNA metabolism
-results in cell death and lymphocyte depletion
What was the original use of Cladribine?
Chemotherapeutic agent used for leukemia
What is an important point to remember about the Cladribine structure?
Prodrug
What is Rituximab approved to treat?
Non-Hodgkin lymphomas
Rheumatoid arthritis
What MS patients should we consider using Rituximab in?
Primary Progressive MS patients
*effective in some
also for Relapsing Remitting MS (RRMS)
What is the MOA of Ocrelizumab?
new drug
Monoclonal antibody that targets CD20 (marker on mature B cells)
*only targets mature B cells, good because we still need B cells
What is the name of the antisense oligonucleotide in clinical trials for MS?
ATL1102
What is the MOA of ATL1102?
Antisense oligonucleotide that targets VLA-4
*predicted to have the same outcome as natalizumab
(oligonucleotides recognize mRNA and prevent production of protein from them)
Which of the following drugs is (are) active in both the periphery and the CNS?
a. dimethyl fumarate
b. natalizumab
c. rituximab
d. teriflunomide
e. none of the above
A. Dimethyl fumarate
What are 2important diagnostic criteria for MS?
Dissemination in Time (DIT)
Dissemination in Space (DIS)
What is Dissemination in Time (DIT)?
regarding MS diagnosis criteria
Time between evidence of new lesions in subsequent MRIs
(30 days)
*damage that has happened more than once over time is required to diagnose MS
What is Dissemination in Space (DIS)?
regarding MS diagnosis criteria
Need to have at least 2 lesions in different areas of the brain at 2 different times to be able to diagnose MS
(damage in more than one place)
True or False: having 1 lesion is enough to diagnose as MS
False, need at least 2
What is the most common type of MS?
Relapsing Remitting MS
How does Secondary Progressive MS present?
Normally is a progression of RRMS
-fewer relapses with continuing disability
Who is more likely to be diagnosed with Primary Progressive MS?
Patients diagnosed later in life
What is Progressive Relapsing MS (PRMS)?
*Least common form
Steadily worsening disease
Later, clear, acute relapses
May have recovery from acute attacks but no remission between relapses
*What is the first choice for MS treatment?
High-dose corticosteroid treatment
(oral or IV based on setting)
Which corticosteroid is used IV for MS and what is the dose?
Methylprednisolone
500mg-1000mg IV daily
3-7 days with or without oral taper over 1-3 weeks
Why might we give an IV corticosteroid to an MS patient?
Want to blast with anti-inflammatory to bring down lesion and reduce the risk of demyelination
What corticosteroid is used outpatient in patients with MS and what is the dose?
Prednisone
1250mg
every other day x 5 doses
no need for taper
*note: 50mg is highest tablet strength, taking a large number of tablets
What are the oral MS medications?
Dimethyl fumarate
Diroximel fumarate
Fingolimod**(only 1st line)
Ozanimod
Ponesimod
Siponimod
Teriflunomide
What are the injectable MS medications?
Interferon beta-1a
Interferon beta -1b
Peginterferon beta-1a
Glatiramer acetate
What are infusion MS medications?
Alemtuzumab
Natalizumab
Ocrelizumab
What is the only drug for primary progressive MS?
Ocrelizumab
What must all MS patients do to prevent the development of progressive multifocal leukoencephalopathy?
Get tested for JCV antibodies
-disease is caused by reactivation of dormant JCV and causes the myelin sheath to break down
What is another important thing all patients with MS should do before starting treatment to prevent their risk of disease?
Get up to date on all vaccines before starting MS treatment because they will be at higher risk for diseases that have vaccines to be deadly after starting treatment
*consider varicella vaccine even if they have never had chicken pox
What vaccines are preferred for patients with MS?
Inactivated vaccines
What are 3 important counseling points for Dimethyl Fumarate, Diroximel Fumarate, and Monomethyl Fumarate?
-Do not open capsule (do not put on food, do not crush or chew)
-Monitor LFTs (hepatotoxicity)
-Monitor CBC (neutropenia)
What are 2 side effects of Dimethyl Fumarate, Diroximel Fumarate, and Monomethyl Fumarate?
Progressive multifocal leukoencephalopathy (PML)
Flushing (can take aspirin before to prevent)
When are Sphingosine 1-Phosphate Receptor Modulators contraindicated?
Past arrhythmia diagnosis
What are the Sphingosine 1-Phosphate Receptor Modulators?
Fingolimod
Ozanimod
Ponesimod
Siponimod
What is an important point to remember when trying to stop Sphingosine 1-Phosphate Receptor Modulators?
Discontinuation can worsen MS symptoms
MAO inhibitors should be avoided with which drug?
Ozanimod
What testing is required before starting Siponimod?
CYP2C9 genotype testing
What side effects may occur with Glatiramer Acetate?
-Lipoatrophy
-Chest pain
-Injection side effects
What treatment may be preferred with pregnancy?
Glatiramer acetate
(teratogenic effects are unknown)
What side effects are associated with interferons?
*Flu-like symptoms
Psychiatric effects (depression, suicidal thinking)
Elevated LFT
Thyroid dysfunction
What assessment should be done before starting interferons?
Mental health assessment
What are the 3 monoclonal antibody drugs?
Alemtuzumab
Natalizumab
Ocrelizumab
What monoclonal antibodies require REMS program to be done?
Alemtuzumab
Natalizumab
What is the only FDA-approved drug for Primary Progressive MS (PPMS)?
Ocrelizumab
Complete vaccinations are required at least how long before starting monoclonal antibody treatment for MS?
6 weeks
Which MS drug has an absolute contraindication with pregnancy?
Teriflunomide
If a patient is taking Teriflunomide and becomes pregnant, what should be done?
Take:
-accelerated elimination cholestyramine
or
-activated charcoal for 11 days
What is the single MS drug approved to treat gait abnormalities/walking speed?
Dalfampridine (Ampyra)
-blocks K channels to prevent cell repolarization
-prolongs action potentials
**may increase walking speed
Why do we only use ER medications and not IR?
IR dosage form and dose escalation is associated with seizures
*contraindicated in patients with seizure history
What are the symptoms of Parkinson’s disease?
TRAP
Tremor
Rigidity
Akinesia (slow movement)
Postural Instability (balance, coordination)
-mask-like appearance
-speech and cognitive deficit, depression
What causes Parkinson’s Disease?
Loss of dopaminergic neurons in the substantia nigra
What % of nigral dopamine neurons are lost in Parkinson’s disease before motor symptoms present?
50% of nigral dopamine neurons
Or: 70-80% of nerve terminals in striatum
Besides loss of dopaminergic neurons, what else is a common characteristic of Parkinson’s disease?
Presence of Lewy Bodies
What are Lewy Bodies?
Dense, spherical protein deposits
-seen in the brains of Parkinson’s patients
-Enriched with fibrillar forms of the protein a-synuclein
Where is it suggested that Parkinson’s disease may begin?
Brainstem
(because this is the first place Lewy bodies have found to show up in)
What area of the brain needs to be affected for classic Parkinson’s symptoms to appear?
Substantia nigra
**undergoes neurodegeneration
What are the 2 pathways that dopamine neurons signal through?
Direct pathway
Indirect pathway
What receptors are involved in the direct pathway of dopamine neuron signaling?
D1 receptors (in the striatum)
What receptors are involved in the indirect pathway of dopamine neuron signaling?
D2 receptors (in the striatum)
What signaling is favored in signaling from the SNpc to D1 and D2 receptors in the striatum?
Thalamocortical signaling
(this is disrupted in PD)
What happens when dopamine is released to the direct and indirect pathways?
Increased signaling from the thalamus to the cortex occurs
-this causes increased motor signaling
When the direct or indirect dopamine pathways are interrupted, what is observed?
Interruption of motor functions
Antimuscarinics are used in Parkinson’s for what purpose?
Adjunct therapy to treat tremor
What is the antimuscarinic used in Parkinson’s?
Benztropine
How do antimuscarinics work in Parkinson’s?
Acetylcholine is excitatory and Dopamine is inhibitory
A loss of dopamine results in excess energy in cholinergic pathways
Cholinergic antagonists help compensate for this
*most effective treatments increase dopaminergic transmission
What drug is considered the “Gold Standard” of Parkinson’s treatment?
L-DOPA
What is L-DOPA?
Precursor of dopamine
How does L-DOPA differ from dopamine?
It is orally active and can enter the CNS
*dopamine cannot because it has a positive charge at neutral pH
What is a common side effect of L-DOPA?
Nausea
What drug can be added to L-DOPA in the combination product “Sinemet”?
Carbidopa
When we co-administer carbidopa, how much can we decrease the dose of L-DOPA by?
4x
Where does carbidopa work?
*Peripherally acting DOPA decarboxylase inhibitor
Where in the body do we want L-DOPA converted to dopamine?
Substantia nigra
*but not the periphery because dopamine cannot cross the BBB
Will carbidopa cross the BBB?
NO
-has a charge, only works in periphery
What are the challenges of L-DOPA treatment?
*On/off oscillations (after years)
*Dyskinesia (right after dose, produces exaggerated motor effects)
Off state (when plasma levels decline, drug may not have an effect)
How can we avoid the challenges of L-DOPA treatment?
Administer in a continuous manner instead of pulsatile
(Subq infusion in trials currently)
How can we avoid limitations associated with the prodrug conversion of L-DOPA?
L-DOPA must be converted to dopamine by DOPA decarboxylase
-the progressive disease and death of dopamine neurons causes patients to become unresponsive to L-DOPA
**We can use dopamine receptor agonists instead
(because postsynaptic dopamine receptors are still present in the striatum)
What are the dopamine receptor agonists?
Apomorphine
Ropinirole
Pramipexole
Rotigotine
What kind of receptor agonist is Apomorphine?
Mixed D1/D2 agonist
When is Apomorphine used?
Late stages of Parkinson’s Disease to provide rapid relief of the off state
Why is the usefulness of Apomorphine limited?
It has potent emetic (vomiting) effects
What kind of receptor agonists are Ropinirole, Pramipexole, and Rotigotine?
D2/D3 agonists
Which Parkinson’s drug is a patch?
Rotigotine
What are the three MAO-B inhibitors?
Selegiline
Rasagiline
Safinamide (reversible)
What is the function of the MAO-B inhibitors?
Inhibit dopamine metabolism
Are MAO-B inhibitors reversible or irreversible?
Irreversible
(propargylamines)
When are MAO-B inhibitors used?
Can be used as initial monotherapy
Can be used as an adjunct to L-DOPA
What is the reversible MAO-B inhibitor?
Safinamide
When is Safinamide used?
Adjunct to L-DOPA/Carbidopa
What are the COMT inhibitors?
Entacapone
Tolcapone
What is the MOA of COMT inhibitors?
Decrease metabolism of L-DOPA in the periphery
Tolcapone: Increases CNS dopamine levels
What drugs are included in the combination product Stalevo?
L-DOPA
Carbidopa
Entacapone
What is bradykinesia?
Slowness of movement
What is the Parkinsonian gait?
Dragging of feet (difficult to get them off the ground)
Width of step shortened
**fall risk
What is an important non-motor symptom of Parkinson’s disease to remember?
Constipation
**dopaminergic interruption has a variety of roles including gut movement
What are some non-pharmacologic therapies for Parkinson’s disease?
-Exercise/physical therapy
-Nutritional counseling
-Occupational therapy
-Psychotherapy/support groups
-Speech therapy
What is the first step that needs to be done in Parkinson’s treatment?
Rule out drug-induced Parkinson’s
What are the 1st line agents for Parkinson’s?
-Dopamine precursor
-Dopamine agonists
-MAO-B inhibitor
What are the 2nd line agents for Parkinson’s disease?
COMT inhibitors
Amantadine
When are dopamine agonists considered first-line?
age < 60 years
Higher risk for dyskinesia
Rank the following drugs in order of the MOST efficacy with motor symptoms to LEAST efficacy with motor symptoms:
Dopamine Agonists
Levodopa/Carbidopa
MAOB-I
Most:
Levodopa/Carbidopa
Dopamine Agonists
MAOB-I
What are the two types of dopamine agonists?
Non-ergot
Ergot
What are the 3 first-line treatment agents for Parkinson’s disease?
Dopamine Precursors (L-DOPA, Carbidopa)
Dopamine Agonists
MAO-B inhibitors
What are the non-ergot drugs?
Pramipexole
Ropinirole
Rotigotine
Apomorphine
What are dopamine agonists used for?
Minimize LD motor fluctuations
Which dopamine agonists are rarely used?
Ergots
*have toxicity
Which drugs can have Impulse Control Disorder (ICD)?
Dopamine Agonists
Which drug can cause insomnia because it is metabolized to a stimulant?
Selegiline
Which drug group in Parkinsons has a risk of serotonin syndrome?
MAO-B inhibitors
*drug-drug interaction
(these minimize dopamine breakdown but can also inhibit breakdown of other neurotransmitters like serotonin)
What are the COMT inhibitors?
Entacapone
Opicapone
Tolcapone
“capone”
When are COMT inhibitors used?
As a combination product to manage symptom fluctuation
Which drug can cause brown/orange urine discoloration as a side effect?
Entacapone
When is Amantadine used?
To manage motor fluctuations in Parkinsons disease
*rarely used monotherapy
What is a common side effect of Amantadine?
Confusion/hallucinations
What are the anticholinergics used in Parkinsons Disease?
Benztropine
Trihexyphenidyl
When are anticholinergics used in Parkinsons disease?
Management of tremor-dominant symptoms in patients <65 years old
What medications can worsen Parkinson’s disease?
Dopamine Antagonists
-Antipsychotics
-Metoclopramide
-Prochlorperazine
-Promethazine
NOTE
Review lecture 6 slide 35
What gender is more likely to get Alzheimer’s disease?
Females
2:1 ratio female:male
What is the neuropathology of Alzheimer’s disease?
Loss of brain volume
Amyloid plaque formation
Neurofibrillary tangle formation
Synapse loss
Where are amyloid plaques located?
Extracellular
Where are neurofibrillary tangles located?
Intracellular
What are Amyloid Plaques made of?
Amyloid-B peptide (AB)
What are neurofibrillary tangles made of?
Hyper-phosphorylated tau
Neuropathology associated with Alzheimer’s disease typically affects what areas of the brain?
Areas of higher cognitive function:
-Entorhinal cortex
-Hippocampus
-Basal forebrain cholinergic systems
-Neocortex
(these have to do with memory, learning, consolidation, and cognition)
Neurons with neurofibrillary tangles and amyloid plaques often develop what?
Destruction of synapses
Destruction of synapses causes what?
Reduced levels of neurotransmitters
*Acetylcholine
-Serotonin
-Norepinephrine
-Dopamine
*Also dysregulated glutamate (toxicity)
What is the key pathogenic molecule in Alzheimer’s disease?
AB or tau?
AB
What gene encodes the AB precursor protein?
APP (amyloid precursor protein)
**mutations in this are linked to early onset Alzheimer’s
What syndrome is associated with Alzheimer’s-like symptoms late in life and why?
Down’s syndrome
*because the APP gene is located on chromosome 21 and patients with Down’s syndrome have an extra copy of this
What is the function of B-secretase and y-secretase?
Release AB peptide from APP (amyloid precursor protein)
What is the function of a-secretase?
Cleaves APP (amyloid precursor protein) in the middle of the AB segment
-releases non-toxic fragment
***this prevents the release of AB which prevents amyloid plaque formation!
What is the difference between AB42 and AB40?
*differ in the number of amino acids in their structure
*AB42 more readily forms amyloid plaques
How can mutations in the APP gene lead to greater amyloid plaque formation?
Mutations favor more cleavage by B- or y-secretase
*this leads to more AB42 production over AP40
What do the presenilin proteins do?
Cleave AB from APP
*mutations in the gene encoding these lead to early onset Alzheimer’s
*mutations lead to production of more AB42 by altering y-secretase cleavage of APP
What are the presenilin proteins components of?
y-secretase complex
What are the 2 presenilin proteins?
PSEN1 and PSEN2
How does AB aggregation effect tau pathology?
Kinase activation leads to tau hyper-phosphorylation
This creates neurofibrillary tangles
Ultimately results in disruption of cytoskeleton and axonal trafficking (synapse transport)
Neurofibrillary tangle formation results in what?
Cytoskeletal defects
The cytoskeletal tracks are disrupted leading to defects in axonal transport and synaptic dysfunction
What is the function of normal tau?
Binds and stabilizes microtubules
*hyperphosphorylation causes tau to fall off and form tangles
How does AB aggregation affect microglial activation?
Increases microglial activation
-microglia release pro-inflammatory cytokines that cause neuroinflammation
-microglia also release reactive nitrogen species and reactive oxygen species that cause oxidative stress
What two things are caused by microglial activation?
Neuroinflammation
Oxidative stress
Individuals with what gene/allele are more likely to develop Alzheimer’s disease?
ApoE4
*note allele 4
Inheritance of what Apo allele decreases the risk of developing Alzheimer’s?
ApoE2
What are the cholinesterase inhibitors used to treat Alzheimer’s disease?
Donepezil
Rivastigmine
Galantamine
What is the function of Donepezil?
Specific, reversible inhibitor of acetylcholinesterase
What is the function of Rivastigmine?
Inhibits acetylcholinesterase AND butyrylcholinesterase
What is the function of Galantamine?
Selective, reversible inhibitor of acetylcholinesterase
AND enhances the action of acetylcholine on nicotinic receptors
What is the anti-glutamatergic therapy used in Alzheimer’s disease?
Memantine
How does Memantine work?
NMDA (glutamate receptor) antagonist
-blocks glutamatergic neurotransmission through noncompetitive mechanism
-reduces excitotoxicity (caused by excess glutamate signaling)
What are the possible targets for disease-modifying therapy of Alzheimer’s disease?
AB generation
AB aggregation
AB clearance
Tau kinase inhibitors
Glutamate-mediated excitotoxicity
Inflammation and Oxidative stress
What do the AB antibodies: Aducanumab, Lecanemab, and Donanemab target?
AB clearance
What radiolabeled agent is used to visualize Alzheimer’s disease?
Florbetapir (18F)
*binds B-amyloid
*visualized by PET scanning
What is the radiolabeled agent specific for tau?
Flortaucipir (18F)
True or False: Not every dementia patient has Alzheimer’s
True
What are the characteristics of Vascular Dementia?
-Impaired judgment or executive function
-Result from brain injury associated with vascular disease or stroke
What are the characteristics of Dementia with Lewy Bodies (DLB)?
-Combination of cognitive decline and Parkinsonian symptoms
-Visual hallucinations
-Cortical Lewy Bodies
What are the characteristics of Frontotemporal Dementia (FTD)?
AKA Pick’s Disease
-Disinhibited behavior
-Tau accumulation (Pick’s bodies)
What percent of patients with epilepsy will experience their first seizure by age 20?
> 80%
What is the percent chance of having epilepsy after having a single seizure?
20%
What is the percent chance of having epilepsy after having 2 seizures?
60%
What is the percent chance of having epilepsy after having 3 seizures?
75%
What are the types of generalized seizures (non-absence types)?
-Myoclonic
-Tonic
-Clonic
-Atonic
-Tonic-Clonic
What is a myoclonic seizure?
Shock-like muscle contraction
(ex: isolated jerking of head, trunk, body)
*isolated jerks
What is a tonic seizure?
Rigidity
-results from increased extensor muscle tone
**occur in children
What is a clonic seizure?
Rapid, repetitive motor activity
*occur in babies and young children
What is an atonic seizure?
Sudden loss of muscle tone
-patient falls if standing
-“drop attacks”
What is a tonic-clonic seizure?
Tonic (rigid) phase immediately followed by Clonic (repetitive activity) stage
“Grand Mal” seizure
What is the most severe seizure type?
Tonic-Clonic
What is a “seizure”?
Paroxysmal disorder of the CNS
-characterized by abnormal cerebral neuronal discharge
**with or without loss of consciousness
What is “epilepsy”?
Repeated seizures
*due to damage, irritation, or chemical imbalance in brain
-leads to sudden, excessive, synchronous electrical discharge
Where does a seizure originate from?
Gray matter
What causes seizures?
Disordered, Synchronous, and Rhythmic firing of brain neurons
“Synchronized Hyperexcitability”
What can prolonged seizures cause?
Ischemia
*because the brain uses more energy and oxygen than it can manufacture
What are the 3 seizure classifications?
Focal onset
Generalized Onset
Unknown Onset
What is the most common classification of seizures?
Focal
What is a Focal seizure?
Seizure activity starts in one area of the brain
“focal point”
Where do focal seizures commonly start?
Temporal lobe
What typically causes Focal seizures?
Some kind of damage to the brain
(disease, trauma, lesion, etc)
What is a Focal to Bilateral seizure?
A focal seizure that progresses to a generalized seizure
-typically by projections to the thalamus
What is a Generalized seizure?
Involves both brain hemispheres and multiple locations in the brain
What is the main cause of a Generalized seizure?
Genetic
What is an important point to remember about Generalized seizures?
Patients are unconscious
What genes indicate that a patient has epilepsy?
GABRA1
GABRB2+3
GABRG2
SCN1A+B
SCN2A
SCN8A
*GABA receptors and Sodium Channels
What does an EEG of a focal seizure look like?
Sharp waves shown only in the electrodes placed where the seizure is coming from on the brain
(less pronounced than generalized, only appears in some rows of the EEG)
What does the EEG of a generalized seizure look like?
Shows involvement of both hemispheres
-crazy peaks along the entire EEG in every row
What are the two types of focal seizures?
Aware
Impaired Awareness
What is the defining factor of Aware type seizures?
No loss of consciousness
What seizure types may involve the subject experiencing auras?
Aware Type Focal seizures
+
Impaired Awareness Focal seizures
What are the symptoms of an Aura associated with a seizure?
Abdominal discomfort
Sense of fear
Unpleasant smell
Abnormal electrical activity
What is a simple partial seizure?
Old term for Aware type focal seizure
What is a complex partial seizure?
Old term for Impaired awareness seizure
What is a postictal state?
Altered state of consciousness after a seizure
*occurs with impaired awareness focal seizures
What type of seizure is an absence seizure?
Generalized
What are the two types of Absence seizures?
Typical
Atypical
What is a Typical Generalized seizure?
Brief loss of consciousness (10-45 seconds)
-staring or eye flickering, often repetitive
**No convulsions, aura, or postictal period
*Begin abruptly
What is an Atypical Generalized seizure?
*Slower onset than typical
**Difficult to control pharmacologically
Do tonic-clonic seizures have an aura?
No aura in the tonic phase!
***can have a brief aura if they are focal-to-bilateral tonic-clonic seizures
What is Status Epilepticus?
Repetitive seizure activity in which the patient does not regain consciousness between seizures
OR
A single seizure lasting > or = 30mins (after 5 minutes it is considered this)
*note: this is a medical emergency
*convulsions occur
What is the therapeutic goal with Status Epilepticus?
Bring seizures under control within 60 mins
True or False:
One seizure is considered epilepsy
False
When can we gradually withdraw epilepsy drugs?
Patients clinically free of seizures for 2-5 years
Which of the following types of convulsions can be preceded by an aura phase?
A. typical absence (petit-mal)
B. primary generalized tonic-clonic
C. focal to bilateral (secondary generalized) tonic-clonic
D. all of the above
C. focal to bilateral (secondary generalized) tonic-clonic
What is a “secondarily generalized” seizure?
old term for Focal-to-Bilateral seizure
What is a paroxysmal depolarizing shift (PDS)?
A large depolarization that triggers a burst of action potentials
What occurs during depolarization?
Influx of cations (ex: Ca+)
-through activation of AMPA and NMDA by glutamate
**Becomes more positive
**Excites the neuron
What occurs during hyperpolarization?
Influx of anions (ex: Cl-)
Efflux of K+
*follows depolarization
*Involves activation of GABA receptors
**Becomes more negative
**Inhibits the neuron
What are the two ways we can reduce excitation?
Reduce glutamate (excitatory neuron leads to excess movements)
Increase GABA (inhibitory interneuron)
Activation of GABA receptors cause what?
Hyperpolarization
**want this with seizures to prevent them
Activation of Glutamate causes what?
Depolarization
What are AMPA and NMDA?
Glutamate-mediated excitatory receptors
*activation is important in depolarization
Which one causes seizures?
Break down of Glutamate
Breakdown of GABA
The breakdown of GABA-mediated inhibition allows action potentials to propagate to distant neurons which causes a spread of seizure activity
-this makes seizures change from focal to secondary generalized
What is a potential trigger of status epilepticus?
Sudden discontinuation of AEDs (anti-epileptic drugs)
What drugs increase the risk for seizures?
**Alcohol
-Theophylline
-CNS stimulants (coffee)
*Bupropion
*Oral contraceptives
-Withdrawal from depressants
*Clozapine
Which of the following occurs during the hyperpolarization phase of a PDS?
A. Influx of Cl- ions resulting from GABA receptor activation
B. Influx of K+ through voltage- and calcium-dependent K+ channels
C. Activation of NMDA receptors
D. All of the above
A. influx of Cl- ions resulting from GABA receptor activation
What is the MOA of anticonvulsant drugs?
Stabilize and reduce neuronal excitability
What are the 5 ways that anticonvulsant drugs reduce excitability?
- Decrease sodium influx and prolong inactivation of their channels
- Reduce calcium influx
- Enhance GABA-mediated neuronal inhibition
- Antagonize excitatory transmitters (glutamate!)
- Other targets (levetiracetam!)
What method of reducing excitability by anticonvulsant drugs is most critical for absence seizures?
Reduction of calcium influx
What are the excitatory presynaptic targets of anticonvulsant drugs?
Na+ channels
Ca+ channels
What are the excitatory post-synaptic targets of anticonvulsant drugs?
NMDA receptors
AMPA receptors
What are the inhibitory presynaptic targets of anticonvulsant drugs?
GABA transporter (GAT-1)
GABA transaminase (GABA-T)
What are the inhibitory post-synaptic targets of anticonvulsant drugs?
GABA A receptors
GABA B receptors
What common structural feature do anticonvulsant drugs share?
Heterocyclic ring structure
What drugs are used to treat Focal Seizures and Generalized Tonic-Clonic seizures?
Hydantoins
What Hydantoins are used to treat focal and tonic-clonic seizures?
Phenytoin*
Fosphenytoin **injectable prodrug
What is the MOA of phenytoin?
Binds and stabilizes the inactive state of Na+ channels
**not isoform selective, works in brain and other body parts
What are two important points about phenytoin elimination kinetics?
Dose-dependent
Has non-linear pharmacokinetics
What do phenytoin, carbamazepine, and phenobarbital do that can cause drug interactions?
Induce liver cytochrome P450
**increases metabolism of other drugs
What are two side effects to remember for phenytoin?
Gingival hyperplasia
Hirsutism
What is the MOA of carbamazepine and oxcarbazepine?
Stabilize inactivated state of Na+ channels
Which iminostilbene has reduced toxicity?
Oxcarbazepine
(less toxic than carbamazepine)
What is the MOA of Lacosamide?
Enhances inactivation of voltage-gated Na+ channels
What drugs target Excitatory Presynaptic Na+ Channels?
Phenytoin
Carbamazepine
Lacosamide
Where do barbiturates and Benzodiazepines bind?
Allosteric regulatory site on GABA A receptor
(directly bind GABA receptor)
What is the MOA of phenobarbital?
Binds an allosteric regulatory site on GABA A receptor
-Increases duration of Cl- channel opening
(enhances GABA signaling)
True or False: primidone is more similar to phenytoin than phenobarbital
True
What are the benzodiazepines?
Diazepam
Clonazepam
What is the MOA of Diazepam and Clonazepam?
Binds an allosteric regulatory site on GABA A receptor
-Increases FREQUENCY of Cl- channel opening
(enhances GABA signaling)
What type of treatment are Diazepam and Clonazepam not useful for?
Chronic treatment
(because of tolerance)
What is clonazepam useful for?
Acute epilepsy treatment
**Absence seizures
What drugs target the inhibitory post-synaptic GABA A receptors?
Phenobarbital
Benzodiazepines
What is ataxia?
Impaired coordination
What is the MOA of Gabapentin and Pregabalin?
Increase GABA release
Decrease Ca+ influx
Reduce glutamate release
**mimic GABA
When is Vigabatrin used?
Adjunct therapy for refractory patients
What is the MOA of Vigabatrin?
Irreversible inhibitor of GABA transaminase (GABA-T)
What is GABA transaminase (GABA-T)?
Enzyme responsible for degrading GABA
*bad
When is Tiagabine used?
Adjunct therapy
What is the MOA of Tiagabine?
Inhibits GABA transporter (GAT-1)
What is the GABA transporter (GAT-1)?
Transporter responsible for transporting GABA out of the system
*bad
What is the function of the NMDA receptor?
Glutamate binding triggers Na+ and Ca+ influx and K+ efflux
What is the function of the AMPA receptor?
Glutamate binding triggers Na+ influx and K+ efflux
What is the MOA of Felbamate?
NMDA receptor antagonist
When is Felbamate used?
3rd line agent for refractory cases
What is an important side effect of Felbamate?
Severe hepatitis
What is the MOA of Topiramate?
AMPA and Kainate receptor antagonist
When is Topiramate used?
Monotherapy or Adjunct
What are the succinimides?
Ethosuximide
What is the MOA of ethosuximide?
Blocks T-type Ca+ channels
What do T-type Ca+ channels do?
Generate the rhythmic discharge of an absence attack
Which of the following statements is TRUE?
A. Tiagabine inhibits GABA transaminase
B. Gabapentin increases Cl- influx in postsynaptic neurons
C. Topiramate is an NMDA receptor antagonist
D. Phenytoin is stabilized by the co-administration of carbamazepine
B
What two drugs have a risk for seizure recurrence with withdrawal?
Phenytoin
Valproate
What is considered “drug-resistant” epilepsy?
Failure of at least two trials of antiseizure medication
What type of drug therapy is used with status epilepticus?
IV
How many attacks are needed to classify Migraine without Aura?
5 attacks
How many attacks are needed to classify Migraine with Aura?
2 attacks
